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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
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  • A61P9/00—Drugs for disorders of the cardiovascular system
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/84—Sulfur atoms
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  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
  • C07D235/26—Oxygen atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
  • C07D235/28—Sulfur atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• the present invention relates to novel substituted imidazole and benzimidazole derivatives useful as histamine H 3 antagonists.
• the invention also relates to pharmaceutical compositions comprising said compounds and their use in treating inflammatory diseases, allergic conditions, obesity, metabolic syndrome and central nervous system disorders.
• the invention also relates to the use of a combination of novel histamine H 3 antagonists of this invention with histamine Hi compounds for the treatment of inflammatory diseases and allergic conditions, as well as pharmaceutical compositions comprising a combination of one or more novel histamine H 3 antagonist compounds of the invention with one or more histamine Hi compounds.
• H 1 , H 2 , H 3 and H 4 are well-identified forms.
• the H 1 receptors are those that mediate the response antagonized by conventional antihistamines.
• H 1 receptors are present, for example, in the ileum, the skin, and the bronchial smooth muscle of humans and other mammals.
• H 2 receptor- mediated responses histamine stimulates gastric acid secretion in mammals and the chronotropic effect in isolated mammalian atria.
• H 4 receptors are expressed primarily on eosinophils and mast cells and have been shown to be involved in the chemotaxis of both cell types.
• H 3 receptor sites are found on sympathetic nerves, where they modulate sympathetic neurotransmission and attenuate a variety of end organ responses under control of the sympathetic nervous system. Specifically, H 3 receptor activation by histamine attenuates nonepinephrine outflow to resistance and capacitance vessels, causing vasodilation.
• Imidazole H3 receptor antagonists are well known in the art. More recently, non-imidazole H3 receptor antagonists have been disclosed in US Patent 6,720,328, and in US Published Applications 2003/0109564, 2004/0097483, 2004/0048843 and 2004/0019099.
• the present invention provides novel compounds of formula I:
• n 2, 3, 4 or 5
• R is R 3 -aryl, R 3 -heteroaryl, R 3 -cycloalkyl, R 3 -heterocycloalkyl, alkyl, haloalkyl, -OR 4 , -SR 4 or -S(O)i -2 R 5 ;
• R 1 is H and R 2 is or R 1 is R 6 - ⁇ henyl and
• R 2 is H; or R 1 and R 2 are independently selected from the group consisting of
• X is -O- or -S-; or R 1 and R 2 , together with the carbon atoms to which they are attached form
• X is -O-, -S- or-NR 7 -; .
• p 1-5;
• Q is -N(R 10 )-. -S- or -O-; q is 1 -4 and r is 1 -4, provided that the sum of q and r is 3-6; s is 1 or 2;
• R 3 is 1-3 substituents independently selected from the group consisting of H, alkyl, halo, OH, alkoxy and -NR 11 R 12 ;
• R 4 is alkyl, arylalkyl or cycloalkyl;
• R 5 is alkyl, -NR 11 R 12 , R 3 -aryl or R 3 -arylalkyl;
• R 6 is 1-3 substituents independently selected from the group consisting of H, alkyl, -CF 3 , halo, -NO 2 , -CN, -C(O)OR 13 -C(O)NR 11 R 12 , -NR 14 R 15 , -OR 13 and haloalkyl;
• R 7 is H, alkyl, -C(O)OR 13 -C(O)NR 11 R 12 Or -C(O)R 13 ;
• each R 8 is independently selected from the group consisting of H, alkyl, cycloalkyl, R 3 -ary
• R 9 is 1-3 substituents independently selected from the group consisting of H, alkyl and cycloalkyl;
• t is O, 1 or 2;
• R 11 and R 12 are independently selected from the group consisting of H, alkyl, cycloalkyl, aryl and arylalkyl;
• R 13 is H, alkyl, cycloalkyl or arylalkyl
• R 14 is H, alkyl, cycloalkyl or arylalkyl
• R 15 is H, alkyl, cycloalkyl, -C(O)OR 13 -C(O)NR 11 R 12 Or-C(O)R 13 ;
• R 16 is H, alkyl, R 3 -cycloalkyl, R 3 -aryl, R 3 -arylalkyl or R 3 -heteroaryl;
• each R 17 is independently selected from the group consisting of H, alkyl, cycloalkyl, R 3 -aryl, R 3 -arylalkyl, R 3 -heteroaryl, R 3 -heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, -C(O)OR 13 -C(O)NR 11 R 12 and -C(O)R 16 .
• This invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising an effective amount of at least one compound of formula I and a pharmaceutically acceptable carrier.
• This invention further provides a method of treating: allergy, allergy-induced airway (e.g., upper airway) responses (e.g., pruritis, sneezing, rhinorrhea, mucosal inflammation; see, for example, McLeod, JPET, 305 (2003) 1037), congestion (e.g., nasal congestion), hypotension, cardiovascular disease, diseases of the Gl tract, hyper- and hypo- motility and acidic secretion of the gastro-intestinal tract, metabolic syndrome, obesity, sleeping disorders (e.g., hypersomnia, somnolence, and narcolepsy), disturbances of the central nervous system, attention deficit hyperactivity disorder (ADHD), hypo- and hyperactivity of the central nervous system (for example, agitation and depression), and/or other CNS disorders (such as Alzheimer's, schizophrenia, and migraine) comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I.
• "Patient” means a mammal, typically a human,
• This invention further provides a pharmaceutical composition comprising an effective amount of a combination of at least one compound of formula I and at least one Hi receptor antagonist in combination with a pharmaceutically acceptable carrier.
• This invention further provides a method of treating allergy, allergy-induced airway (e.g., upper airway) responses, and/or congestion (e.g., nasal congestion), comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a combination of at least one compound of formula I and at least one Hi receptor antagonist.
• Kits comprising a compound of formula I in a pharmaceutical composition and a separate Hi receptor antagonist in a pharmaceutical composition in a single package are also contemplated.
• the invention provides a pharmaceutical composition comprising effective amount of a combination of at least one compound of formula I - O -
• kits comprising in a single package a compound of formula I in a pharmaceutical composition and one or more agents for treating obesity or metabolic syndrome in one or more pharmaceutical compositions.
• R is preferably R 3 -phenyl, R 3 -pyridyl, alkylthio, alkoxy, alkyl or haloalkyl. More preferably, R is pyridyl, especially 2-pyridyl. R 3 is preferably hydrogen, both on the "R" substituent and on the phenyl ring shown in formula I. R 1 and R 2 preferably combine with the carbons to which they are attached to form an R 6 -substituted phenyl ring. R 6 is preferably halo, more preferably fluoro. When R 1 and R 2 are not joined to form a ring, one of R 1 and R 2 is preferably R 6 - phenyl and the other is H. X is preferably -O-.
• Z is structure a), i.e., optionally substituted piperidinyl or optionally substituted pyrrolidinyl.
• R 8 substituents are present selected from the group consisting of alkyl, hydroxyl, -NHC(O)alkyl, - C(O)NR 11 R 12 -C(O)alkyl, -C(O)Oalkyl and heterocycloalkyl; each R 17 is preferably H.
• R 8 is heterocycloalkyl, it is preferably piperidinyl or pyrrolidinyl.
• alkyl represents straight and branched carbon chains and contains from one to six carbon atoms
• aryl including the aryl portion of arylalkyl
• aryl represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl or naphthyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment
• arylalkyl represents an aryl group, as defined above, bound to an alkyl group, as defined above, wherein said alkyl group is bound to the compound
• cycloalkyl represents saturated carbocyclic rings of from 3 to 6 carbon atoms
• halo represents fluoro, chloro, bromo and iodo
• haloalkyl means an alkyl as
• Chloroalkyl and fluoroalkyl refer to alkyl groups substituted by either chloro or fluoro groups, respectively, for example fluoroalkyl represents a straight or branched alkyl chain substituted by 1 to 5 fluoro atoms, which can be attached to the same or different carbon atoms, e.g., -Cht ⁇ F, -CHF2, -CF3, -CH 2 CF 3 and -CF 2 CF 3 ,- heteroaryl represents cyclic groups, having 1 to 4 heteroatoms selected from
• said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms.
• the rings do not contain adjacent oxygen and/or sulfur atoms.
• Examples include but are not limited to isothiazolyl, isoxazolyl, oxazolyl, furazanyl, triazolyl, tetrazolyl, thiazolyl, thienyl, furanyl (furyl), pyrrolyl, pyrazolyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridyl (e.g., 2-, 3-, or 4-pyridyl), pyridyl N-oxide (e.g., 2-, 3-, or 4-pyridyl N-oxide), triazinyl, pteridinyl, indolyl (benzopyrrolyl), pyridopyrazinyl, isoquinolinyl, quinolinyl, naphthyridinyl; all available substitutable carbon and nitrogen atoms can be substituted as defined; heterocycloalkyl represents a saturated, carboc
• upper airway usually means the upper respiratory system ⁇ i.e., the nose, throat, and associated structures.
• ⁇ generally means a therapeutically effective amount.
• substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
• stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
• purified refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof.
• purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
• protecting groups When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic
• composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• prodrugs and solvates of the compounds of the invention are also contemplated herein.
• the term "prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of Formula I or a salt and/or solvate thereof.
• a discussion of prodrugs is provided in T. Higuchi and V.
• Solvate means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
• Solvate encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
• “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
• Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
• the compounds of Formula I can form salts which are also within the scope of this invention.
• Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
• the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
• zwitterions inner salts may be formed and are included within the term "salt(s)" as used herein.
• Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
• Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
• Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
• Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
• esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n- propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxy methyl), aryl (for example, phenyl optionally substituted with, for example, halogen, or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or
• One or more compounds of the invention may also exist as, or optionally converted to, a solvate.
• Preparation of solvates is generally known.
• M. Caira etal, J. Pharmaceutical ScL, 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
• Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1 ⁇ , article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001).
• a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
• Analytical techniques such as, for example I. R, spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
• All stereoisomers for example, geometric isomers, optical isomers and the like
• of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs
• those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4- pyridyl and 3-pyridyl).
• Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
• the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
• the use of the terms "salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
• a line drawn into a ring means that the indicated bond may be attached to any of the substitutable ring carbon atoms.
• the compounds of this invention are ligands for the histamine H 3 receptor.
• the compounds of this invention can also be described as antagonists of the H 3 receptor, or as H 3 antagonists.
• the compounds of this invention can be combined with an Hi receptor antagonist (i.e., the compounds of this invention can be combined with an Hi receptor antagonist in a pharmaceutical composition, or the compounds of this invention can be administered with an Hi receptor antagonist).
• Hi receptor antagonists useful in the methods of this invention can be classified as ethanolamines, ethylenediamines, alkylamines, phenothiazines or piperidines.
• Hi receptor antagonists include, without limitation: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, warmthlastine, trimeprazine and triprolidine.
• Other compounds can readily be evaluated to determine activity at Hi
• the Hi receptor antagonist is used at its known therapeutically effective dose, or the Hi receptor antagonist is used at its normally prescribed dosage.
• said Hi receptor antagonist is selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, warmthlastine, trimeprazine or triprolidine.
• said Hi receptor antagonist is selected from: astemizole, azatadine, azelastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, carebastine, descarboethoxyloratadine, diphenhydramine, doxylamine, ebastine, fexofenadine, loratadine, levocabastine, mizolastine, norastemizole, or terfenadine.
• said Hi receptor antagonist is selected from: azatadine, brompheniramine, cetirizine, chlorpheniramine, carebastine, descarboethoxyloratadine, diphenhydramine, ebastine, fexofenadine, loratadine, or norastemizole. Even more preferably, said Hi antagonist is selected from loratadine, descarboethoxyloratadine, fexofenadine or cetirizine. Still even more preferably, said Hi antagonist is loratadine or descarboethoxyloratadine.
• allergy-induced airway responses are treated.
• the antagonists can be administered simultaneously or sequentially (first one and then the other over a period of time). In general, when the antagonists are administered sequentially, the H 3 antagonist of this invention (compound of formula I) is administered first.
• metabolic syndrome refers to a combination of risk factors for cardiovascular disease (CVD) identified in the National Cholesterol Education Program's Adult Treatment Panel III report. See for example the discussion by Grundv et al in Circulation, 109 (2004), 433-438.
• CVD cardiovascular disease
• the components of metabolic syndrome are: 1 ) abdominal obesity; 2 ⁇ atherogenic dyslipidemia; 3) raised blood pressure; 4) insulin reistance; 5) proinflammatory state; and 6) prothrombotic state.
• CB 1 antagonists include CB 1 antagonists, NPY5 antagonists, MCH antagonists, MC4R agonists and serotonin uptake inhibitors.
• the compounds of Formula I can be prepared in many ways known to those skilled in the art. Following are typical procedures for preparing various compounds; other procedures may also be applicable and the procedures may be modified to prepare other compounds within the scope of Formula I. One skilled in the art will recognize that one route will be optimal depending on the choice of appendage substituents. Additionally, one skilled in the art will recognize that in some cases the order of steps has to be controlled to avoid functional group incompatibilities.
• Ci/mmol Curie/mmol (a measure of specific activity)
• Step 1 Compound 1 is reacted with an aniline derivative 2 in a suitable solvent such as THF or dioxane, preferably dioxane, at a temperature sufficient to effect the reaction, preferably 50 to 150° C, to give compound 3.
• Step 2 The nitro group of compound 3 is reduced to the amine 4 using hydrogen gas in the presence of a suitable catalyst such as Pd/C, PtO 2 , Raney nickel, preferably Raney Nickel, in a suitable solvent such as methanol, ethanol, or isopropanol, preferably methanol or ethanol.
• a suitable catalyst such as Pd/C, PtO 2 , Raney nickel, preferably Raney Nickel
• Step 3 The primary amine of compound 4 is acylated by reaction with a carboxylic acid in the presence of coupling agents such as DEC and HOBT in a suitable solvent such as ether, THF, or CH 2 CI 2 , preferably CH 2 CI 2 to give compound 5.
• the amine can be acylated by an acid chloride in the presence of a base.
• step 4 In step 4, compound 5 in acetic acid is heated for a sufficient time for cyclization to occur.
• Compound 6 is reacted with an ⁇ , ⁇ -dihaloalkane in a suitable solvent such as acetone, THF, ether or the like, preferably acetone, in the presence of a base such as Na 2 COs or K 2 CO 3 , preferably K 2 CO 3 , at a temperature from 0 to 65°C to give compound 7 wherein Y is halo.
• a suitable solvent such as acetone, THF, ether or the like, preferably acetone
• Step 6 A solution of compound 7 in a suitable solvent such as CH 3 CN, THF, ether, or the like, preferably CH 3 CN, is treated with a tertiary amine base such as Et 3 N, DIPEA or the like, preferably DIPEA, followed by the ZH, wherein Z is as defined above. The reaction is then heated at a temperature from 0 to 100°C to give compound 8.
• a suitable solvent such as CH 3 CN, THF, ether, or the like, preferably CH 3 CN
• a tertiary amine base such as Et 3 N, DIPEA or the like, preferably DIPEA
• Z is as defined above.
• Substituted imidazole analogs can be prepared as shown in Scheme 2, wherein R, R 3 X, n and Z are as defined above, and wherein R 1 and R 2 are as defined above, but do not form a ring.
• Step 1 Compound 9, known in the literature, is reacted with an ⁇ , ⁇ -dihaloalkane in a suitable solvent such as acetone, THF, ether or the like, preferably acetone, in the presence of a base such as Na 2 COs or K 2 CO 3 , preferably K2CO 3 , at a temperature from 0 to 65°C to give compound 10.
• a suitable solvent such as acetone, THF, ether or the like, preferably acetone
• a base such as Na 2 COs or K 2 CO 3 , preferably K2CO 3
• Step 2 A solution of compound 10 in a suitable solvent such as CH 3 CN, THF, ether, or the like, preferably CH 3 CN, is treated with a tertiary amine base such as EtsN, DIPEA or the like, preferably DIEPA, followed by the ZH, wherein Z is as defined above. The reaction is then heated at a temperature from 0 to 100°C to give compound 11.
• a suitable solvent such as CH 3 CN, THF, ether, or the like, preferably CH 3 CN
• a tertiary amine base such as EtsN, DIPEA or the like, preferably DIEPA
• Step 1 In step 1 , compound 12 is reacted with an ⁇ , ⁇ -dihaloalkane in a suitable solvent such as acetone, THF, ether or the like, preferably acetone, in the presence of a base such as Na2CO 3 or K 2 CO 3 , preferably K 2 CO 3 , at a temperature from 0 to 65 0 C to give compound 13, wherein Y is halo.
• Step 2 A solution of compound 13 in a suitable solvent such as CH 3 CN, THF, ether, or the like, preferably CH 3 CN, is treated with a tertiary amine base such as Et3N, DIPEA or the like, preferably DIPEA, followed by the ZH, wherein Z is as defined above. The reaction is then heated at a temperature from 0 to 10fJ 0 C to give compound 14.
• a suitable solvent such as acetone, THF, ether or the like, preferably acetone
• a base such as Na2CO 3 or K 2
• Step 3 The nitro group of compound 14 is reduced to the amine 15 using H 2 gas in the presence of a suitable catalyst such as Pd/C, Pt ⁇ 2 , or Raney nickel, preferably Raney Nickel, in a suitable solvent such as methanol, ethanol, or isopropanol, preferably methanol or ethanol.
• a suitable catalyst such as Pd/C, Pt ⁇ 2 , or Raney nickel, preferably Raney Nickel
• a suitable solvent such as methanol, ethanol, or isopropanol, preferably methanol or ethanol.
• Other reduction methods well known to those versed in the art are also suitable.
• Step 4 Compound 15 is reacted with 16 in a suitable solvent such as THF or dioxane, preferably dioxane, at a temperature sufficient to effect the reaction, preferably 50 to 150° C, to give compound 17.
• Step 5 In a similar manner to Step 3, the nitro group of compound 17 is reduced to the amine to obtain compound 18.
• Step 7 A solution of 19 in a suitable solvent such as DMSO, DMF or the like is treated with a base such as K 2 CO 3 or the like and an alkylating agent R 4 L, in which L is Cl, Br or I, or a mesylate or sulfonate, at a temperature of 0 to 100 0 C, preferably from 25 to 75°C, to give 20.
• Step 4 A solution of compound 5 (2.1 g, 6.50 mmol) in 15 ml of acetic acid was heated at 120 0 C under N 2 for 2Oh. After cooling to RT, the product was concentrated in vacuo to give 6.
• Step 5 A solution of compound 5 (2.1 g, 6.50 mmol) in 15 ml of acetic acid was heated at 120 0 C under N 2 for 2Oh. After cooling to RT, the product was concentrated in vacuo to give 6.
• Step 6 To 48-wells of a 96-well block of 1-ml glass tubes were added compound 7 (0.01 g, 0.026 mmol), MeCN (0.5 ml), and DIPEA (0.104 mmol).
• Example 2A was prepared:
• Step 1
• Step 1 K 2 CO 3 (6.0 g, 43.2 mmol) was added to a solution of 15 (2.0 g, 14.4 mmol) and 16 (1.4 ml, 14.4 mmol) in acetone (50 ml) at 25 0 C. The mixture was refluxed under N 2 for 2Oh. After cooling to RT, the products were filtered, the filtrate was concentrated in vacuum and purified by 4OM Biotage Cartridge to give V7_. Yield: 97%.
• Step 2 To a solution of 17 (3.0 g, 13.9 mmol) and piperidine (2.8 ml, 27.8 mmol) in 30 ml of n-butanol at 25 0 C, Na 2 CO 3 (1.4 g, 13.9 mmol) and NaI (0.04 g, 0.3 mmol) were added. The mixture was stirred at 100 0 C under N 2 for 2Oh. After cooling to RT, the products were filtered, the filtrate was concentrated in vacuum and purified by 40M Biotage Cartridge to give .18. Yield: 100%.
• Step 3 Ra-Ni (1.0 g) was added to a MeOH (30 ml) solution of 1j3 (3.7 g, 14.0 mmol) at 25 0 C in a 500 ml hydrogenation bottle. The mixture was hydrogenated at 50 Psi H 2 for 2Oh. The products were then filtered through celite, and concentrated in vacuum to give 19. Yield: 85%.
• Step 4 To a solution of 19 (2.8 g, 11.9 mmol) in 1,4-dioxane (30 ml) was added 2,5- difluoronitrobenzene (1.9 g, 11.9 mmol) at 25 0 C. The mixture was refluxed under N 2 for 72h.
• Step 5 The same procedure as step 3 was used to obtain 2 ⁇ _. Yield: 94%.
• Step 6 To a solution of 21 (0.5 g, 1.5 mmol) in THF (10 ml) was added 1 ,1'- thiocarbonyldiimidazole (0.7 g, 3.9 mmol) at 25 0 C. The mixture was stirred at 70 0 C under N 2 for 2Oh.
• Example 4C was prepared:
• Example 4D Using a similar procedure but replacing 1 ,1'-thiocarbonyldiimidazole with 1 ,1'- carbonyldiimidazole in step 6 and using ethyl iodide in step 7, Example 4D was prepared:
• the source of the H 3 receptors in this experiment was guinea pig brain.
• the animals weighed 400-600 g.
• the brain tissue was homogenized with a solution of 50 mM Tris, pH 7.5.
• the final concentration of tissue in the homogenization buffer was 10% w/v.
• the homogenates were centrifuged at 1 ,000 x g for 10 min. in order to remove clumps of tissue and debris.
• the resulting supematants were then centrifuged at 50,000 x g for 20 min. in order to sediment the membranes, which were next washed three times in homogenization buffer (50,000 x g for 20 min. each).
• the membranes were frozen and stored at -70 0 C until needed.
• Compounds of formula I have a Kj within the range of about 1 to about 1000 nM.
• Preferred compounds of formula I have a K,- within the range of about 1 to about 100 nM. More preferred compounds of formula I have a K,- within the range of about 1 to about 10 nM.
• the compound of Example 1 EE has a Ki of 1 nM.
• the term "at least one compound of formula I” means that one to three different compounds of formula I may be used in a pharmaceutical composition or method of treatment. Preferably one compound of formula I is used.
• “at least one Hi receptor antagonist” means that one to three different Hi antagonists may be used in a pharmaceutical composition or method of treatment. Preferably, one Hi antagonist is used.
• inert, pharmaceutically acceptable carriers can be either solid or liquid.
• Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
• the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
• Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A.
• Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
• a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
• solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
• liquid forms include solutions, suspensions and emulsions.
• the compounds of the invention may also be deliverable transdermally.
• the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
• the compound is administered orally.
• the pharmaceutical preparation is in a unit dosage form.
• the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
• the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 150 mg, preferably from about 1 mg to about 75 mg, more preferably from about 1 mg to about 50 mg, according to the particular application.
• the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
• the amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.
• a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 75 mg/day, in two to four divided doses.
• the two active components may be co-administered simultaneously or sequentially, or a single pharmaceutical composition comprising a W 2
• Hs antagonist and an Hi antagonist in a pharmaceutically acceptable carrier can be administered.
• the components of the combination can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc.
• the dosage of the Hi antagonist can be determined from published material, and may range from 1 to 1000 mg per dose. When used in combination, the dosage levels of the individual components are preferably lower than the recommended individual dosages because of the advantageous effect of the combination.
• kits comprising in a single package, one container comprising an H3 antagonist in a pharmaceutically acceptable carrier, and a separate container comprising an Hi antagonist in a pharmaceutically acceptable carrier, with the H 3 and Hi antagonists being present in amounts such that the combination is therapeutically effective.
• a kit is advantageous for administering a combination when, for example, the components must be administered at different time intervals or when they are in different dosage forms.
• Combinations with other agents for treating obesity or metabolic syndrome are prepared and administered in an analogous manner.

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